Yield of the Genetic Test in Suspected Catecholaminergic Polymorphic Ventricular Tachycardia and Implications for Test Interpretation

Background: Pathogenic variants account for ≈60% of clinically definite cases of catecholaminergic polymorphic ventricular tachycardia. However, the rate of rare benign variants identified in the general population remains a challenge for genetic test interpretation. Therefore, we examined the results of the genetic test among patients referred for commercial genetic testing and examined factors impacting variant interpretability.

Methods: Frequency and location comparisons were made for variants identified among 1355 total patients of varying clinical certainty and 60 706 Exome Aggregation Consortium controls. The impact of the clinical phenotype on the yield of variants was examined. Six in silico tools were assessed using patient- and control-derived variants.

Results: A total of 18.2% (218/1200) of patients referred for commercial testing hosted rare variants, statistically less than the 59% (46/78) yield among clinically definite cases, resulting in a much higher potential genetic false discovery rate among referrals considering the 3.2% background rate of rare, benign variants. Exclusion of clearly putative pathogenic variants further complicates the interpretation of the next novel variant. Exonic/topologic analyses revealed overrepresentation of patient variants in exons covering only one third of the protein. In silico tools largely failed to show evidence toward enhancement of variant interpretation.

Conclusions: Current expert recommendations have resulted in increased use of genetic testing in patients with questionable clinical phenotypes. Using the largest to date catecholaminergic polymorphic ventricular tachycardia patient versus control comparison, this study highlights important variables in the interpretation of variants to overcome the 3.2% background rate that confounds variant interpretation.